Alzheimer's disease (AD) is a progressive and fatal brain disease that is the most common form of dementia. Its characteristic pathology includes extracellular amyloid plaques that form as a result of abnormal clearance and/or increased production of amyloid-β peptides (Aβ) that are released from the amyloid precursor protein (APP).1, 2 It is likely that the toxic forms of Aβ are not the intact plaques but rather soluble oligomers and prefibrillar assemblies that lead to oxidative stress and neuronal destruction.3 Metal ions, particularly Cu1+/2+ and Zn2+ but also Fe2+/3+, have been implicated in both processes related to Aβ pathology: peptide aggregation and formation of reactive oxygen species (ROS) that lead to oxidative stress.4 Exactly how metals mediate these processes is not fully appreciated, and questions remain about the protective versus harmful roles that individual metals play under different conditions and at different stages of disease progression.
It is speculated that both APP and Aβ may have normal roles in copper homeostasis.5, 6 It has also been shown in vitro that Aβ can act as an antioxidant by quenching free radicals and by chelating Cu in a manner that minimizes its reactivity for catalyzing OH. from H2O2 via the Fenton reaction (Eq. 1).7, 8 Cu++H2O2→Cu2++OH.  Eq. 1Other evidence, however, suggests that Aβ-Cu complexes are pro-oxidant and directly culpable of neurotoxicity. In vitro, Aβ in the presence of Cu or Fe and reducing agents like ascorbate produces H2O2, which can subsequently react with the reduced metal to produce hydroxyl radicals via the Fenton reaction.9-11 Metal-mediated H2O2 generation appears at an early stage during in vitro Aβ aggregation,11 which supports the notion that soluble Aβ-Cu species are responsible for the oxidative damage that is one of the earliest pathological events in AD.12 Furthermore, copper has been shown to intensify Aβ toxicity in primary cortical neurons.9, 10, 13 Like Cu2+, Zn2+ also promotes Aβ aggregation in vitro, but the Zn-induced aggregates appear to be neuroprotective, perhaps by displacing Cu2+ and thereby suppressing H2O2 generation.14-16 
An emerging hypothesis to reconcile the seemingly contradictory evidence related to metals, Aβ, and oxidative stress is that metal binding and Aβ aggregation may represent an initial, protective response to dampen ROS production. Excessive H2O2 production and an overburden of Cu could eventually push the system into a vicious cycle that switches Aβ-Cu activity from antioxidant to pro-oxidant.17 During this stage, metal exchange with Zn2+ could promote further Aβ aggregation as a defense against Cu-induced damage. While strong chelating agents are known to reverse metal-induced aggregates, this model suggests that disaggregating plaques alone could have the unintended consequence of exacerbating oxidative damage.17 
Metal chelating agents have appeared as a compelling strategy for Alzheimer's disease therapies.18 In particular, 8-hydroxyquinoline (8HQ) derivatives clioquinol and PBT2 have shown promising results in mouse models and in phase IIa clinical trials of Alzheimer's patients.19, 20 These compounds inhibit metal-induced Aβ aggregation and ROS generation.21 It is thought that their primary mechanism of action is to redistribute extracellular metal ions to intracellular stores where they are required for biochemical function.19 
While these reports are encouraging for the further development of metal-targeted compounds for neurodegenerative disease, concerns remain for the unintended consequences of manipulating metal distribution in the brain. New reagents are needed that can function as metal-binding agents that mitigate the damaging effects of metals while preserving their beneficial effects.